Immediate Hypersensitivity Reactions to Biologic Drugs in Children with Inflammatory Bowel Diseases.

INTRODUCTION: The increased use of biologic drugs (BDs) may lead to an increase in immediate hypersensitivity reactions (I-HSRs) in pediatric patients with inflammatory bowel disease (IBD). Our aim was to assess I-HSRs to BDs in pediatric IBD, examining frequency, clinical features, management, and associated risk factors. METHODS: All children diagnosed with IBD at our institution between January 1, 2006, and August 1, 2023, and who developed I-HSRs related to any BD were included in the study. RESULTS: In a study of 197 pediatric IBD patients, 61 used BD. Among these, 52.4% were male, with a median diagnosis age of 145 months (13-215). Out of a total of 1,679 administrations, 6 patients developed I-HSRs (5 with infliximab, 1 with adalimumab), resulting in a frequency of 9.8% per patient and 0.36% per administration. Of these, 66.7% were cases of Type 1 HSRs (skin test positivity n = 1), while the rest were infusion-related reactions (anti-drug antibody positivity n = 4), all of which were mild to moderate in severity. In the age and gender-adjusted logistic regression model, the presence of any comorbid allergic disease was significantly associated with the occurrence of I-HSR (aOR = 8.35; 95% CI = 1.24-56.38; p = 0.029). CONCLUSION: The frequency of I-HSRs to BDs in children with IBD is not rare but not severe in the long term. The presence of any comorbid allergic disease is a risk factor for the development of I-HSRs to BDs.

Are Medical Students and Primary Health-care Professionals Aware of Neonatal Cholestasis and Acholic Stool.

Early diagnosis of biliary atresia (BA) and the timing of Kasai hepatic portoenterostomy are associated with improved survival rates of the native liver. Acholic stool is a major and earliest sign of BA. We evaluated the awareness and recognition of medical students and primary health care professionals (PHCPs) about neonatal cholestasis and acholic stool as a marker of BA. The knowledge of students and PHCP about prolonged jaundice and acholic stool was evaluated through a questionnaire. In the first step, 5 questions evaluating the knowledge of prolonged jaundice were asked. The sixth question was "Have you ever seen acholic stool before?" Following this question, stool color cards with 9 colors were shown, and participants were asked "Which of the following stool pictures would you define as acholic?" A total 724 students and 88 PHCPs were included in the study. In both groups, about half of the participants could not answer the first 4questions related to prolonged jaundice and cholestasis correctly. Twenty-four percent of the students and 11.4% of PHCP answered correctly to all of the stool colors. The rate of correct answers to acholic stool colors were approximately 43.9%-87.6% and 23.9%-86.4% for students and PHCP, respectively. Whitish acholic stool colors were better known than mild yellowish pale stool colors. The percentages of recognition were less than about 50% for these stool colors. This study showed that recognition and awareness of prolonged jaundice are low, and acholic stool is not well known. This may lead to delay in diagnosis. Considering the international success of stool color cards, using stool color cards will improve the outcomes of biliary atresia in our country as well.

A Classification for Gastric Outlet Obstruction in Childhood: Extending Beyond Infantile Hypertrophic Pyloric Stenosis.

BACKGROUND/AIMS:  Gastric outlet obstruction (GOO) is a rare condition in childhood, with the exception of infantile hypertrophic pyloric stenosis (IHPS). However, no classification exists from a pediatric gastroenterologist's perspective. MATERIALS AND METHODS:  The patients with a diagnosis of GOO between 2009 and 2020 were reviewed retrospectively. We classified the patients according to GOO: presence of clinical findings accompanied by radiological and/or endoscopic findings; clinical status: intractable nonbilious postprandial vomiting alone or with abdominal pain, early satiety, weight loss, postprandial abdominal distension, and malnutrition; radiology: delayed gastric emptying and dilated stomach; endoscopy: nonbilious gastric contents after 6-8 hours of emptying and/or failed pyloric intubation; physical examination: visible gastric peristalsis. RESULTS:  A total of 30 GOO patients (15 patients with IHPS, 1 patient with annular pancreas, 4 patients with gastric volvulus, 2 patients with duodenal atresia, 2 patients with antral web, 1 patient with late-onset hypertrophic pyloric stenosis (LHPS) had surgical treatment, and remaining 5 patients had medical treatment) were enrolled to the study. The median age was 8 months (range: 3 months-16 years), and 14 patients were female. Mitochondrial disorders, LHPS, metabolic disorders, and eosinophilic gastrointestinal system diseases were added to Sharma's GOO classification, and the classification has been expanded. CONCLUSION:  This is the first and largest study of GOO in children. From the perspective of pediatric gastroenterology, new diseases will be addressed, and definitions will be highlighted with our classification for GOO in childhood.

Genetic landscape of pediatric acute liver failure of indeterminate origin.

BACKGROUND AND AIMS: Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, the main causes are viral infections (12%-16%) and inherited metabolic diseases (14%-28%). Yet, in up to 50% of cases the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition. APPROACH AND RESULTS: With this international, multicenter observational study, patients (0-18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed. RESULTS: In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF. WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (41%), and in children with recurrent acute liver failure (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8), and DGUOK (n=7) were the most frequent findings. When categorizing, the most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%), and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplantation. CONCLUSIONS: This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics.

Is the Pediatric Eosinophilic Esophagitis Symptom Score v2.0 reliable for telemedicine?

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease. Telemedicine is a healthcare technology used when a patient is separated by distance. The reliability of the Pediatric Eosinophilic Esophagitis Symptom Score, version 2.0 (PEESS v2.0) for telemedicine applications, has not been studied yet. Therefore, we aimed to evaluate the reliability of PEESS v2.0 for telemedicine. METHODS: We sent a telesurvey using questionnaires via electronic telecommunication as the telemedicine method. Children with EoE and their parents were asked to complete PEESS v2.0 with the telesurvey method (unsynchronized with the physician) and attend in-person visits one week apart. Intraclass correlation (ICC), Wilcoxon, and Bland-Altman tests were used as reliability analyses. Reliability was defined as a strong agreement between the measurements in ICC ≥ 0.8 and a p-value of ≤0.05 and no statistically significant difference between the scores of the two methods in the Wilcoxon and Bland-Altman analyses, i.e. a p-value of >0.05. RESULTS: The total scores of children and parents were higher in in-person visits than in the telesurvey (Wilcoxon tests, p ≤ 0.05). Bland- Altman analysis showed that the mean difference in total scores between the two methods was significant for both children and parents (p ≤ 0.05). ICC levels for the children and parent scores for the entire group ranged from 0.595 to 0.763 (moderate agreement). DISCUSSION: Unsynchronized telesurvey use of PEESS v2.0 is unreliable both for children and parents. We suggest testing the reliability of chosen telemedicine methods before using them in clinical and research practice.

Portal Hypertension in Children: A Tertiary Center Experience in Turkey.

Purpose: Portal hypertension (PH) and its complications have a significant impact on morbidity and mortality. This study aimed to evaluate the etiology; clinical, laboratory, and endoscopic findings; treatment approaches; long-term outcomes; and prognosis of pediatric PH. Methods: This retrospective study included 222 pediatric patients diagnosed with PH between 1998 and 2016, and data encompassing clinical, laboratory, and radiological features; treatments; and complications were analyzed. Results: The most common causes of PH were portal vein thrombosis (20.3%), progressive familial intrahepatic cholestasis (18.9%), and biliary atresia (12.2%). Among the enrolled patients, 131 (59.0%) were included in the cirrhotic group and 91 (41.0%) in the non-cirrhotic group. Hepatomegaly and increased transaminase levels were more frequent in the cirrhotic group than in the non-cirrhotic group. Additionally, portal gastropathy, esophageal varices, and variceal bleeding were more frequent in the non-cirrhotic group, whereas ascites, hepatopulmonary syndrome and hepatic encephalopathy were more common in the cirrhotic group. The incidence of hepatomegaly was higher in the presinusoidal group than in the prehepatic group (p<0.001). Hyperbilirubinemia was more frequent in the prehepatic group (p=0.046). The frequency of esophageal varices was similar between the prehepatic and presinusoidal groups; however, variceal bleeding was more frequent in the prehepatic group (p=0.002). Conclusion: Extrahepatic portal vein obstruction, genetic-metabolic diseases, and biliary atresia were the most prevalent causes of PH in our country. In patients with PH, hepatomegaly, increased transaminase levels, and synthesis dysfunction were suggestive of cirrhotic PH. Notably, PH in patients without cirrhosis might be more severe than that in those with cirrhosis.

The frequency of Duchenne muscular dystrophy/Becker muscular dystrophy and Pompe disease in children with isolated transaminase elevation: results from the observational VICTORIA study.

Introduction: Elevated transaminases and/or creatine phosphokinase can indicate underlying muscle disease. Therefore, this study aims to determine the frequency of Duchenne muscular dystrophy/Becker muscular dystrophy (DMD/BMD) in male children and Pompe disease (PD) in male and female children with isolated hypertransaminasemia. Methods: This multi-center, prospective study enrolled patients aged 3-216 months with serum alanine transaminase (ALT) and/or aspartate transaminase (AST) levels >2× the upper limit of normal (ULN) for ≥3 months. Patients with a known history of liver or muscle disease or physical examination findings suggestive of liver disease were excluded. Patients were screened for creatinine phosphokinase (CPK) levels, and molecular genetic tests for DMD/BMD in male patients and enzyme analysis for PD in male and female patients with elevated CPK levels were performed. Genetic analyses confirmed PD. Demographic, clinical, and laboratory characteristics of the patients were analyzed. Results: Overall, 589 patients [66.8% male, mean age of 63.4 months (standard deviation: 60.5)] were included. In total, 251 patients (188 male and 63 female) had CPK levels above the ULN. Of the patients assessed, 47% (85/182) of male patients were diagnosed with DMD/BMD and 1% (3/228) of male and female patients were diagnosed with PD. The median ALT, AST, and CPK levels were statistically significantly higher, and the questioned neurological symptoms and previously unnoticed examination findings were more common in DMD/BMD patients than those without DMD/BMD or PD (p < 0.001). Discussion: Questioning neurological symptoms, conducting a complete physical examination, and testing for CPK levels in patients with isolated hypertransaminasemia will prevent costly and time-consuming investigations for liver diseases and will lead to the diagnosis of occult neuromuscular diseases. Trial Registration: Clinicaltrials.gov NCT04120168.

Food-induced immediate response of the esophagus in pediatric eosinophilic esophagitis.

BACKGROUND: Food-induced immediate response of the esophagus (FIRE) is a new phenomenon that has been described in eosinophilic esophagitis (EoE) patients. It is suspected when unpleasant symptoms occur suddenly on contact of the triggering food with the esophageal surface and recur with repeated exposures. It can often be mistaken for pollen-food allergy syndrome (PFAS) and solid food dysphagia. Data on FIRE is limited to one survey study and case reports, and there are no screening studies conducted on either adults or children with EoE. In this study, we aimed to screen children aged ≥7 years old with EoE for FIRE. METHODS: Demographic data were collected from medical records. A questionnaire about FIRE was applied to all participants. Skin prick tests were done on suspected patients to identify the triggering foods. FIRE is defined as suitable clinical symptoms with suspected food allergen exposure. RESULTS: A total of 78 patients (74.4% male, median age: 13.5 years) were included. Unpleasant and recurrent symptoms distinct from dysphagia with specific foods were reported in 16.7% of the patients, all of whom had concomitant allergic rhinitis (AR). The symptoms described by almost all patients were oropharyngeal itching and tingling (PFAS: 15.3%) excluding only one patient reporting retrosternal narrowing and pressure after specific food consumption (FIRE: 1.2%). CONCLUSIONS: Although definitive conclusions regarding the true prevalence of FIRE cannot be made, it does not seem to be common as PFAS. However, it deserves questioning particularly in the presence of concurrent AR and/or PFAS in children with EoE.

Growth, tolerance and safety outcomes with use of an extensively hydrolyzed casein-based formula in infants with cow's milk protein allergy.

Objective: To evaluate growth, tolerance and safety outcomes with use of an extensively hydrolyzed casein-based formula (eHCF) in infants with cow's milk protein allergy (CMPA). Methods: A total of 226 infants (mean ± SD age: 106.5 ± 39.5 days, 52.7% were girls) with CMPA who received eHCF comprising at least half of the daily dietary intake were included. Data on anthropometrics [weight for age (WFA), length for age (LFA) and weight for length (WFL) z-scores] were recorded at baseline (visit 1), while data on infant feeding and stool records, anthropometrics and Infant Feeding and Stool Patterns and Formula Satisfaction Questionnaires were recorded at visit 2 (on Days 15 ± 5) and visit 3 (on Days 30 ± 5). Results: From baseline to visit 2 and visit 3, WFA z-scores (from -0.60 ± 1.13 to -0.54 ± 1.09 at visit 2, and to -0.44 ± 1.05 at visit 3, p < 0.001) and WFL z-scores (from -0.80 ± 1.30 to -0.71 ± 1.22 at visit 2, and to -0.64 ± 1.13 at visit 3, p = 0.002) were significantly increased. At least half of infants never experienced irritability or feeding refusal (55.7%) and spit-up after feeding (50.2%). The majority of mothers were satisfied with the study formula (93.2%), and wished to continue using it (92.2%). Conclusions: In conclusion, eHCF was well-accepted and tolerated by an intended use population of infants ≤ 6 months of age with CMPA and enabled adequate volume consumption and improved growth indices within 30 days of utilization alongside a favorable gastrointestinal tolerance and a high level of parental satisfaction.

Interim results from an ongoing, open-label, single-arm trial of odevixibat in progressive familial intrahepatic cholestasis.

Background & Aims: PEDFIC 2, an ongoing, open-label, 72-week study, evaluates odevixibat, an ileal bile acid transporter inhibitor, in patients with progressive familial intrahepatic cholestasis. Methods: PEDFIC 2 enrolled and dosed 69 patients across two cohorts; all received odevixibat 120 µg/kg per day. Cohort 1 comprised children from PEDFIC 1, and cohort 2 comprised new patients (any age). We report data through 15 July 2020, with Week 24 of PEDFIC 2 the main time point analysed. This represents up to 48 weeks of cumulative exposure for patients treated with odevixibat from the 24-week PEDFIC 1 study (cohort 1A) and up to 24 weeks of treatment for those who initiated odevixibat in PEDFIC 2 (patients who received placebo in PEDFIC 1 [cohort 1B] or cohort 2 patients). Primary endpoints for this prespecified interim analysis were change from baseline to Weeks 22-24 in serum bile acids (sBAs) and proportion of positive pruritus assessments (≥1-point drop from PEDFIC 2 baseline in pruritus on a 0-4 scale or score ≤1) over the 24-week period. Safety monitoring included evaluating treatment-emergent adverse events (TEAEs). Results: In cohort 1A, mean change from PEDFIC 1 baseline to Weeks 22-24 of PEDFIC 2 in sBAs was -201 µmol/L (p <0.0001). For cohort 1B and cohort 2, mean changes from odevixibat initiation to weeks 22-24 in sBAs were -144 and -104 µmol/L, respectively. The proportion of positive pruritus assessments in the first 24-week period of PEDFIC 2 was 33%, 56%, and 62% in cohorts 1A, 1B, and 2, respectively. Most TEAEs were mild or moderate. No drug-related serious TEAEs occurred. Conclusions: Odevixibat in patients with progressive familial intrahepatic cholestasis was generally well tolerated and associated with sustained reductions in sBAs and pruritus. Clinical Trials Registration: This study is registered at ClinicalTrials.gov (NCT03659916). Impact and Implications: Disrupted bile flow is a hallmark feature of patients with progressive familial intrahepatic cholestasis and can result in build-up of bile constituents in the liver with spill over into the bloodstream; other effects that patients can experience include extremely itchy skin, and because not enough bile reaches the gut, patients can have problems digesting food, which may lead to poor growth. Odevixibat is an orally administered medication that shunts bile acids away from the liver. The current study, called PEDFIC 2, suggested that odevixibat can improve the problematic signs and symptoms of progressive familial intrahepatic cholestasis and was generally safe for patients.

A novel pediatric Eosinophilic Esophagitis Symptoms and Adaptive Behavior Scale for different ages: GaziESAS v2.0.

BACKGROUND: High-quality scales (HQS) suitable that measure symptoms and adaptive behaviors (AB) with proven validity and reliability are needed for different age groups of children with eosinophilic esophagitis (EoE). OBJECTIVE: To develop a high-quality pediatric EoE symptoms and AB scale for different age groups. METHODS: Children (7-11 years), teens (12-18 years), and parents of 2-18-year-old children with EoE were included. A HQS should have encompassed: the identification of domain and item generation; content validity (CnV) and field test for construct validity (CsV) and reliability. Convergent validity (CgV) was examined for CsV. Correlations between the Pediatric Eosinophilic Esophagitis Symptom Score, version 2.0 (PEESS v2.0) and Gazi University Eosinophilic Esophagitis Symptoms and Adaptive Behavior Scale (GaziESAS) version 2.0 (v2.0) were examined for CgV. Reliability was determined through internal consistency (Cronbach-α) and test-retest reliability (intraclass correlation coefficients: ICC). RESULTS: Nineteen children, 42 teens, and 82 parents completed the study. GaziESAS v2.0 was composed of 20 items with two main domains: symptoms (subdomains: dysphagia and nondysphagia) and AB. CnV indexes were excellent for all items. The CgV varied from good to excellent correlation (r = 0.6 to r = 0.9). GaziESAS v2.0 showed good reliability (Cronbach-α >0.7 and ICC >0.6). CONCLUSION: GaziESAS v2.0 is the first pediatric HQS that measures the frequency of symptoms and AB in EoE within the last month with separate forms for children, teens, and parents.

The significance of MUAC z-scores in diagnosing pediatric malnutrition: A scoping review with special emphasis on neurologically disabled children.

This review by a panel of pediatric gastroenterology-hepatology-nutrition and pediatric neurology experts aimed to address the significance of mid-upper arm circumference (MUAC) assessment in diagnosis of pediatric malnutrition. Specifically, the potential utility of recently developed MUAC z-score tape in clinical practice for larger patient populations was addressed including the neurologically disabled children. In accordance with the evidence-based data, four statements were identified by the participating experts on the utility of MUAC z-score tape, including (1) MUAC z-scores correlate with body mass index (BMI) and weight for height/length (WFH/l) z-scores in diagnosing malnutrition; (2) MUAC z-score tape offers a higher sensitivity to diagnose the mild and moderate malnutrition and better ability to track the changes in nutritional status over time than the other single datapoint measurements; (3) Using single-step MUAC z-score tape in children with cerebral palsy (CP) seems to provide more reliable data on anthropometry; and (4) The clinical value of the tool in classifying secondary malnutrition in CP should be investigated in large-scale populations. In conclusion, enabling single-step estimation of nutritional status in a large-scale pediatric population regardless of age and within a wide range of weight, without formal training or the need for ancillary reference charts and calculators, MUAC z-tape offers a favorable tool for easier and earlier diagnosis of pediatric malnutrition. Nonetheless, further implementation of MUAC z-score screening in larger-scale and/or special populations is necessary to justify its utility in relation to other primary anthropometric indicators in diagnosis of malnutrition as well as in treatment monitoring in the community and hospital setting.

Oropharyngeal Dysphagia in Children with Eosinophilic Esophagitis.

Dysphagia is the most troublesome symptom of eosinophilic esophagitis (EoE). This study aimed to investigate oropharyngeal dysphagia in children with EoE and possible related factors. Children with a definite diagnosis of EoE were included in the study. Medical and feeding histories were recorded. A disease control level was determined for each child. An oral structure examination, the Turkish version of the Mastication and Observation Evaluation (T-MOE), the Pediatric version of the Eating Assessment Tool-10 (PEDI-EAT-10) and the 3-oz water swallow test were applied in screening for oropharyngeal dysphagia. Fifty-two children participated in the study. Oropharyngeal dysphagia took the form of abnormal swallowing (PEDI-EAT-10 score ≥ 4) and increased aspiration risk (PEDI- EAT-10 score ≥ 13) in 51.9% and 25.0% of the children, respectively. Seven children failed the 3-oz water swallow test. Abnormal swallowing and aspiration risk were significantly higher in children with prolonged mealtimes, impaired chewing function, and uncontrolled disease (p < 0.05). Chewing function was the most important risk factor for abnormal swallowing and increased aspiration (R2 = 0.36, R2 = 0.52, p < 0.001, respectively). Oropharyngeal dysphagia is common in children with EoE and associated with increased aspiration risk in a subpopulation. Uncontrolled disease, prolonged mealtimes, and impaired chewing function may provide clues for oropharyngeal dysphagia in EoE.

Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a group of inherited paediatric liver diseases resulting from mutations in genes that impact bile secretion. We aimed to evaluate the effects of odevixibat, an ileal bile acid transporter inhibitor, versus placebo in children with PFIC. METHODS: Patients eligible for this 24-week, randomised, double-blind, completed, phase 3 study were paediatric outpatients diagnosed with PFIC1 or PFIC2 who had pruritus and elevated serum bile acids at screening. Patients were randomly assigned (1:1:1) using an interactive web-based system to once a day oral placebo, odevixibat 40 µg/kg, or odevixibat 120 µg/kg. Randomisation was done in a block size of six and stratified by PFIC type and patient age; patients, clinicians, and study staff were blinded to treatment allocation. Patients were enrolled at one of 33 global sites. Two primary endpoints were evaluated: proportion of positive pruritus assessments (PPAs; ie, scratching score of ≤1 or ≥1-point decrease as assessed by caregivers using the Albireo observer-reported outcome [ObsRO] PRUCISION instrument) over 24 weeks, and proportion of patients with serum bile acid response (ie, serum bile acids reduced by ≥70% from baseline or concentrations of ≤70 µmol/L) at week 24. Efficacy and safety were analysed in randomly allocated patients who received one or more doses of study drug. This study is registered with ClinicalTrials.gov, NCT03566238. FINDINGS: Between June 21, 2018, and Feb 10, 2020, 62 patients (median age 3·2 [range 0·5-15·9] years) were randomly allocated to placebo (n=20), odevixibat 40 µg/kg per day (n=23), or odevixibat 120 µg/kg per day (n=19). Model-adjusted (least squares) mean proportion of PPAs was significantly higher with odevixibat versus placebo (55% [SE 8] in the combined odevixibat group [58% in the 40 µg/kg per day group and 52% in the 120 µg/kg per day group] vs 30% [SE 9] in the placebo group; model-adjusted mean difference 25·0% [95% CI 8·5-41·5]; p=0·0038). The percentage of patients with serum bile acid response was also significantly higher with odevixibat versus placebo (14 [33%] of 42 patients in the combined odevixibat group [10 in the 40 µg/kg per day group and four in the 120 µg/kg per day group] vs none of 20 in the placebo group; adjusting for stratification factor [PFIC type], the proportion difference was 30·7% [95% CI 12·6-48·8; p=0·0030]). The most common treatment-emergent adverse events (TEAEs) were diarrhoea or frequent bowel movements (13 [31%] of 42 for odevixibat vs two [10%] of 20 for placebo) and fever (12 [29%] of 42 vs five [25%] of 20); serious TEAEs occurred in three (7%) of 42 odevixibat-treated patients and in five (25%) of 20 placebo-treated patients. INTERPRETATION: In children with PFIC, odevixibat effectively reduced pruritus and serum bile acids versus placebo and was generally well tolerated. Odevixibat, administered as once a day oral capsules, is a non-surgical, pharmacological option to interrupt the enterohepatic circulation in patients with PFIC. FUNDING: Albireo Pharma.

Long-Term Outcomes of Patients With Progressive Familial Intrahepatic Cholestasis After Biliary Diversion.

OBJECTIVES: Progressive familial intrahepatic cholestasis is a heterogeneous group of genetic disorders characterized by disrupted bile homeostasis. Patients with this disease typically present with cholestasis and pruritus early in life and often progress to end-stage liver disease. The clinical symptoms that patients with progressive familial intrahepatic cholestasis encounter are usually refractory to medical treatment. Although the effects of biliary diversion surgery on native liver survival are not exactly known, this procedure may provide a positive impact on pruritus and laboratory parameters in these patients. MATERIALS AND METHODS: We retrospectively evaluated the clinical and laboratory characteristics of patients with progressive familial intrahepatic cholestasis who underwent partial external biliary diversion between 2002 and 2020 at our center. Diagnosis of progressive familial intrahepatic cholestasis was made by clinical, biochemical, and histopathological characteristics as well as genetic testing. RESULTS: Nine patients were included in the study. Five patients required liver transplant during follow-up, with 4 having liver transplant as a result of endstage liver disease (median interval of 5 years). In 1 patient, partial external biliary diversion was performed 1.5 years after liver transplant for severe diarrhea, metabolic acidosis, and hepatic steatosis. Four patients did not require liver transplant during follow-up (median follow-up time of 7.6 years). Pruritus responded well to partial external biliary diversion in all patients. Among laboratory values evaluated 6 months after biliary diversion, only albumin showed significant improvement. CONCLUSIONS: Partial external biliary diversion had favorable results on long-term follow-up. This procedure can provide the relief of pruritus and delay the requirement for liver transplant in patients with progressive familial intrahepatic cholestasis. In our view, partial external biliary diversion should be considered the first-line surgical management for patients with this disease.

Partial External Biliary Diversion for Severe Diarrhea After Liver Transplant in Patients with Progressive Familial Intrahepatic Cholestasis Type 1.

Progressive familial intrahepatic cholestasis is a heterogeneous group of autosomal recessive disorders, and liver transplant is the only curative treatment. A biliary diversion operation for disruption of enterohepatic circulation in patients with progressive familial intrahepatic cholestasis type 1 without cirrhosis is another option. We present a pediatric patient with progressive familial intrahepatic cholestasis type 1 who underwent liver transplant due to end-stage liver disease. After transplant, diarrhea and growth retardation complications resolved after partial external biliary diversion surgery.

Two Cases With Neonatal Cholestasis and Renal Disorders Due to DCDC2 Mutation.

Ciliopathies are a heterogeneous group of diseases that are observed after deterioration of the ciliary structures on the cell surface that facilitate communication with the environment. Both liver and kidney involvement are frequently observed in this disease. Recently, a doublecortin domain containing protein 2 (DCDC2) mutation in a ciliopathy disease group was identified. Here, we present 2 patients with this mutation and with neonatal cholestasis and renal involvement.

Diagnostic value of plasma lysosphingolipids levels in a Niemann-Pick disease type C patient with transient neonatal cholestasis.

OBJECTIVES: Niemann-Pick disease type C (NPC) is a lysosomal storage disease due to impaired intracellular lipid trafficking caused by biallelic pathogenic variants in NPC1 or NPC2 genes. NPC is classified according to the age of onset of neurological manifestations. Cholestatic liver disease can be transient or lead to liver failure. Accompanying neurological findings can be observed at any age. In this report, an infant with a homozygous pathogenic variant in NPC1 gene whose diagnosis was eventually confirmed by specific biomarkers is described. CASE PRESENTATION: A sixteen-day-old male was admitted to hospital with prolonged jaundice. He had mild hepatosplenomegaly, conjugated hyperbilirubinemia, elevated liver transaminases, and mild hypoalbuminemia. Cholestasis resolved spontaneously and patient was readmitted due to progressive hepatosplenomegaly without any neurologic findings when he was 8 months old. Molecular investigations detected homozygous c.1123A > C (p.Thr375Pro) pathogenic variant in NPC1 gene. NPC-specific lysosomal biomarkers such as Lysosphingomyelin and Lysosphingomyelin-509 were elevated, confirming the diagnosis. CONCLUSIONS: The clinical features of NPC are highly heterogeneous, from disease severity or age of onset to disease progression. Patients presenting with transient neonatal cholestasis and should be regularly followed for neurodevelopmental status and visceromegaly. In the case of variants of unknown significance in NPC1 gene, lysosomal biomarkers play an important role when genetic analyses are inconclusive.

Expected or unexpected clinical findings in liver glycogen storage disease type IX: distinct clinical and molecular variability.

OBJECTIVES: To reveal the different clinical presentations of liver glycogen storage disease type IX (GSD IX), which is a clinically and genetically heterogeneous type of glycogenosis. METHODS: The data from the electronic hospital records of 25 patients diagnosed with liver GSD IX was reviewed. Symptoms, clinical findings, and laboratory and molecular analysis were assessed. RESULTS: Of the patients, 10 had complaints of short stature in the initial presentation additionally other clinical findings. Elevated serum transaminases were found in 20 patients, and hepatomegaly was found in 22 patients. Interestingly, three patients were referred due to neurodevelopmental delay and hypotonia, while one was referred for only autism. One patient who presented with neurodevelopmental delay developed hepatomegaly and elevated transaminases during the disease later on. Three of the patients had low hemoglobin A1C and fructosamine values that were near the lowest reference range. Two patients had left ventricular hypertrophy. Three patients developed osteopenia during follow-up, and one patient had osteoporosis after puberty. The most common gene variant, PHKA2, was observed in 16 patients, 10 variants were novel and six variants were defined before. Six patients had variants in PHKG2, two variants were not defined before and four variants were defined before. PHKB variants were found in three patients. One patient had two novel splice site mutations in trans position. It was revealed that one novel homozygous variant and one defined homozygous variant were found in PHKB. CONCLUSIONS: This study revealed that GSD IX may present with only hypotonia and neurodevelopmental delay without liver involvement in the early infantile period. It should be emphasized that although liver GSDIX is thought of as a benign disease, it might present with multisystemic involvement and patients should be screened with echocardiography, bone mineral densitometry, and psychometric evaluation.

Recommendations for Clinical Decision-making in Children with Type 1 Diabetes and Celiac Disease: Type 1 Diabetes and Celiac Disease Joint Working Group Report

It is well-known that in children with type 1 diabetes (T1D), the frequency of Celiac disease (CD) is increased due to mechanisms which are not fully elucidated but include autoimmune injury as well as shared genetic predisposition. Although histopathologic examination is the gold standard for diagnosis, avoiding unnecessary endoscopy is crucial. Therefore, for both clinicians and patients' families, the diagnosis of CD remains challenging. In light of this, a joint working group, the Type 1 Diabetes and Celiac Disease Joint Working Group, was convened, with the aim of reporting institutional data and reviewing current international guidelines, in order to provide a framework for clinicians. Several controversial issues were discussed: For CD screening in children with T1D, regardless of age, it is recommended to measure tissue transglutaminase-immunoglobulin A (tTG-IgA) and/or endomysial-IgA antibody due to their high sensitivity and specificity. However, the decision-making process based on tTG-IgA titer in children with T1D is still debated, since tTG-IgA titers may fluctuate in children with T1D. Moreover, seronegativity may occur spontaneously. The authors' own data showed that most of the cases who have biopsy-proven CD had tTG-IgA levels 7-10 times above the upper limit. The decision for endoscopy based solely on tTG-IgA levels should be avoided, except in cases where tTG-IgA levels are seven times and above the upper limit. A closer collaboration should be built between divisions of pediatric endocrinology and gastroenterology in terms of screening, diagnosis and follow-up of children with T1D and suspicious CD.